Pharmaceutically active 9-chloroprostaglandins

ABSTRACT

Compounds of the formula ##STR1## wherein the 9-chlorine atom can be in the α-or β-position, 
     A is --CH 2  --CH 2  -- or cis--CH═CH--, 
     B is --CH 2  --CH 2 ,--, trans--CH═CH--, or --CH.tbd.C--, W is hydroxymethylene or 
     D and E together represent a direct bond or 
     D is a straight-chain or branched alkylene group of 1-10 carbon atoms, optionally substituted by fluorine, and 
     E is oxygen or sulfur or a direct bond, and 
     R 4  is hydroxy or hydroxy etherified or esterified as defined for W above; 
     R 5  is a C 1-10  hydrocarbon aliphatic group; a C 1-10  hydrocarbon aliphatic group substituted by aryl, a substituted aryl as defined for R 2  above, or halogen; or cycloalkyl, substituted cycloalkyl, aryl, substituted aryl or aromatic heterocyclic, all as defined for R 2  above; 
     or a physiologically acceptable salt thereof with a base when R 1  is OH, 
     have valuable pharmacologoical properties.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 07/096,232 filed Sep.8, 1987 now U.S. Pat. No. 5,079,259, which is a continuation of06/754,702 now abandoned filed Jul. 15, 1985, which is a continuation of06/581,741 now abandoned filed Feb. 16, 1984, which was a divisional of06/387,140 filed Jun. 10, 1982, now U.S. Pat. No. 4,444,788, which is acontinuation-in-part of U.S. application Ser. No. 215,762, filed on Dec.10, 1980 now abandoned, whose disclosures are incorporated by referenceherein.

BACKGROUND OF THE INVENTION

The present invention relates to novel 9-chloroprostaglandinderivatives, a process for their preparation and their use as medicinalagents.

From the very voluminous state of the art of prostaglandins and theiranalogs, they are well known to be suitable for the treatment ofmammals, including man, because of their biological and pharmacologicalproperties. Their use as medicinal agents, however, frequentlyencounters difficulties. Most of the natural prostaglandins possess aperiod of effectiveness too brief for therapeutic purposes, since theyare too quickly metabolically degraded by various enzymatic processes.All of the attempted structural alterations in these molecules usuallyhave as a goal increasing their duration of activity as well as theirselectivity of effectiveness.

SUMMARY OF THE INVENTION

It is accordingly an object of this invention to provide novel9-chloroprostaglandin derivatives exhibiting an excellent specificity ofeffectiveness, an improved activity, a longer duration of activity thannatural prostaglandins, and a suitability especially for oraladministration.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained by this invention by providing9-chloroprostane derivatives of Formula I ##STR2## wherein the9-chlorine atom can be in the α- or β-position,

R₁ is OR₂ wherein R₂ is hydrogen, alkyl, cycloalkyl, aryl or aheterocyclic residue; or is NHR₃ wherein R₃ is an acid residue orhydrogen;

A is --CH₂ --CH₂ -- or cis--CH═CH--;

B is --CH₂ --CH₂ --, trans--CH═CH--, or --C═C--;

W is free or functionally modified hydroxymethylene or a free orfunctionally modified ##STR3## group, wherein the OH-group can be in theα- or β-position D and E together are a direct bond; or D isstraight-chain or branched-chain alkylene of 1-10 carbon atoms,optionally substituted by fluorine, and E is oxygen, sulfur or a directbond;

R₄ is free or functionally modified hydroxy;

R₅ is a hydrocarbon aliphatic group, optionally substituted by halogen;cycloalkyl; optionally substituted aryl; or a heterocyclic group;

and, when R₁ is hydroxy, the physiologically compatible salts thereofwith bases.

DETAILED DISCUSSION

Suitable alkyl groups R₂ include straight chain or branched alkyl of1-10 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl, heptyl, hexyl, decyl, etc. Thealkyl groups R₂ can optionally be mono- to polysubstituted (e.g., by 2-4substituents) by halogen, C₁₋₄ -alkoxy, optionally substituted aryl oraroyl, each of 6-10 C atoms, di-C₁₋₄ -alkylamino, or tri-C₁₋₄-alkylammonium. Single substitution is preferred. Examples ofsubstituents include fluorine, chlorine, bromine, phenyl, dimethylamino,diethylamino, methoxy, ethoxy, etc. Preferred alkyl groups R₂ are thoseof 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl,dimethylaminopropyl, isobutyl, butyl, etc. Suitable substituents for thesubstituted aryl or aroyl substituents include those mentioned below assubstituents for the R₂ aryl groups.

Aryl groups R₂ can be substituted or unsubstituted and generally are of6-10 C atoms, e.g., phenyl, 1-naphthyl, or 2-naphthyl. These can besubstituted by 1-3 halogen atoms (e.g., F, Cl, Br), a phenyl group, 1-3alkyl groups of 1-4 carbon atoms each, a chloromethyl, fluoromethyl,trifluoromethyl, carboxy, hydroxy, or alkoxy group of 1-4 carbon atoms.Substitutents of the 3- and 4-positions of the phenyl ring arepreferred, for example, by fluorine, chlorine, alkoxy, ortrifluoromethyl, or in the 4-position by hydroxy.

Suitable cycloalkyl groups R₂ can contain 4-10, preferably 5 or 6 carbonatoms in the ring. The rings can be substituted by alkyl groups of 1-4carbon atoms, e.g., by 1-3 such alkyl groups. Examples includecyclopentyl, cyclohexyl, methylcyclohexyl, adamantyl, etc.

Suitable heterocyclic groups R₂ include 5- or 6-membered heterocycles,preferably aromatic, containing at least 1 hetero atom, e.g., 1-2 suchatoms, preferably nitrogen, oxygen or sulfur. Examples of suchequivalent heterocycles are 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, andothers.

The acid residue R₃ is any of the many known physiologically compatibleacid residues. Preferred acids are organic, hydrocarbon carboxylic acidsand sulfonic acids of 1-15 carbon atoms of the aliphatic,cycloaliphatic, aromatic, aromatic-aliphatic, etc. series. Since thisacid residue is not critical, many equivalents exist and may be utilizedas well, e.g., those of the heterocyclic series. These acids can besaturated, unsaturated and/or polybasic and/or substituted inconventional manner. Examples of substituents include alkyl, hydroxy,alkoxy, oxo, amino, halogen, etc. The following carboxylic acids can becited by way of example: formic acid, acetic acid, propionic acid,butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproicacid, enanthic acid, capyrlic acid, pelargonic acid, capric acid,undecylic acid, lauric acid, tridecylic acid, myristic acid,pentadecylic acid, trimethylacetic acid, diethylacetic acid,tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid,cyclohexylacetic acid, cyclopropanecarboxylic acid,cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid,methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroaceticacid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid,morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoicacid, benzoic acids substituted by halogen, trifluoromethyl, hydroxy,alkoxy or carboxy groups, nicotinic acid, isonicotinic acid,furan-2-carboxylic acid, cyclopentylpropionic acid, etc. Particularlypreferred acyl groups are those of up to 10 carbon atoms. Examples ofsuitable sulfonic acids include methanesulfonic acid, ethanesulfonicacid, isopropylsulfonic acid, β-chloroethanesulfonic acid,butanesulfonic acid, cyclopentanesulfonic acid, cyclohexanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid,p-chlorobenzenesulfonic acid, N,N-dimethylaminosulfonic acid,N,N-diethylaminosulfonic acid, N,N-bis(β-chloroethyl)-aminosulfonicacid, N,N-diisobutylaminosulfonic acid, N,N-dibutylaminosulfonic acid,pyrrolidino-, piperidino-, piperazino-, N-methylpiperazino-, andmorpholinosulfonic acids.

The hydroxy groups in W and R₄ can be functionally modified, forexample, by etherification or esterification, wherein the free ormodified hydroxy group in W can be in the α- or β-position.

Suitable ether and acyl residues are fully conventional and well knownto persons skilled in the art. In general, these conventional protectivegroups include, e.g., those disclosed in Mc. Omie. Ed., ProtectiveGroups in Organic Chemistry, Plenum Press, N. Y., 1973, whose disclosureis incorporated by reference herein. Among these many equivalents,preferred are ether residues which can be readily split off, such as,for example, tetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl,trimethylsilyl, dimethyl-tert-butylsilyl, and tribenzylsilyl. Suitableacyl residues are those recited in connection with R₃ above; especiallyworth mentioning, for example, are acetyl, propionyl, butyryl, andbenzoyl.

Suitable hydrocarbon aliphatic groups R₅ include straight-chain orbranched, saturated or unsaturated such residues, preferably saturatedresidues, of 1-10, especially 1-6 carbon atoms, which can optionally besubstituted by optionally substituted aryl, e.g., the R₂ aryl groupsdefined above, substituted and unsubstituted, and by halogen as alsodefined above for R₂ alkyl substitution. Examples include methyl, ethyl,propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl,butenyl, isobutenyl, propenyl, pentenyl, benzyl, m-chlorobenzyl, andp-chlorobenzyl groups.

Suitable R₅ cycloalkyl, substituted or unsubstituted aryl andheterocyclic groups are in accordance with the foregoing discussion ofthe corresponding R₂ groups.

The alkylene group D can be straight chain or branched, saturated orunsaturated. It can be an alkylene of 1-10, especially 1-5 carbon atoms,which can be optionally substituted by 1-3 fluorine atoms. Saturatedresidues are preferred. Examples include methylene,fluoromethylenedifluoromethylene, ethylene, 1,2-propylene,ethylethylene, trimethylene, tetramethylene, pentamethylene,1,1-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene,1-methyltrimethylene, 1-methylene-ethylene, 1-methylenetetramethylene,etc.

B preferably is trans--CH═CH--.

R₅ and/or D/E can also be preferably chosen so that the lower chaincontains an additional double bond, preferably at the 18-position (PGnomenclature). They can also independently be preferably chosen so thatthe 16-position is substituted by one or two alkyl groups, e.g., methylor ethyl, preferably methyl, and/or the 19-position is substituted byalkyl, e.g., methyl or ethyl, preferably methyl.

Inorganic and organic bases are suitable for the salt formation, and areknown to those skilled in the art for the preparation of physiologicallycompatible salts. Examples include alkali metal hydroxides, such assodium and potassium hydroxide, alkaline earth hydroxides, such ascalcium hydroxide, ammonia, amines, such as ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,tris(hydroxymethyl)methylamine, etc.

The present invention furthermore relates to a process for thepreparation of the 9-chloroprostane derivatives of Formula I of thisinvention, wherein, conventionally,

a compound of Formula II ##STR4## wherein

the OH-group can be in the α- or β-position,

R₁, B, D, E, and R₅ are as defined above, and

free OH-groups in R₄ and W, as defined above, are blocked,

(a) is reacted via an intermediate sulfonic acid ester, with a chlorideof Formula III, R₆ Cl, wherein R₆ is lithium, sodium, potassium, ortetraalkylammonium wherein each alkyl is of 1-6 carbon atoms, or

(b) is chlorinated using a carbon tetrachloride/triphenylphosphinereagent,

and, optionally, in the reaction products obtained in reactions (a) or(b), in any desired sequence, blocked hydroxy groups are liberated,and/or free hydroxy groups are esterified, and/or double bonds arehydrogenated, and/or an etherified and/or esterified carboxy group (R₁=OR₂) is saponified, and/or a free carboxy group (R₁ =OH) is esterified,and/or a free carboxy group (R₁ =OH) is converted into an amide (R₁=NHR₃).

The conversion of the compounds of Formula II into 9-sulfonic acidesters takes place conventionally using an alkylsulfonyl chloride orarylsulfonyl chloride in the presence of an amine, e.g., pyridine ortriethylamine, at temperatures of -60° to +100° C., preferably -20° to+50° C. The nucleophilic substitution of the 9-sulfonate by a chlorineatom takes place using an alkali metal chloride, preferably lithiumchloride or tetraalkylammonium chloride, tetrabutylammonium chloridebeing preferred, in an inert solvent, such as, for example,dimethylformamide, dimethylacetamide, dimethyl sulfoxide,dimethoxyethane, tetrahydrofuran, etc., at temperatures of 0° to 100°C., preferably 20° to 80° C.

The compounds of Formula II are converted to the compounds of Formula Iwith carbon tetrachloride and triphenylphosphine in an inert solvent,such as, for example, dimethylformamide, dimethylacetamide,acetonitrile, methylene chloride, etc. at temperatures of 0° to 80° C.,preferably 20° to 45° C.

Functionally modified hydroxy groups are liberated by followingconventional methods. For example, hydroxy blocking groups, e.g.,tetrahydropyranyl, can be split off in an aqueous solution of an organicacid, e.g., oxalic acid, acetic acid, propionic acid, and others, or inan aqueous solution of an inorganic acid, e.g., hydrochloric acid. Toimprove solubility, a water-miscible inert organic solvent is suitablyadded. Examples of suitable organic solvents are alcohols, such asmethanol and ethanol, and ethers, such as dimethoxyethane, dioxane, andtetrahydrofuran. Tetrahydrofuran is preferably employed. Thesplitting-off step is preferably conducted at temperatures of 20° to 80°C.

The acyl groups can be saponified, for example, with alkali metal oralkaline earth carbonates or hydroxides in an alcohol or in an aqueoussolution of an alcohol. Suitable alcohols are aliphatic alcohols, suchas, for example, methanol, ethanol, butanol, etc., preferably methanol.Examples of alkali metal carbonates and hydroxides are the potassium andsodium salts. The potassium salts are preferred. Suitable examples ofalkaline earth carbonates and hydroxides are calcium carbonate, calciumhydroxide, and barium carbonate. The reaction takes place at -10° to+70° C., preferably at about +25° C.

The introduction of the ester group OR₂ as R₁, wherein R₂ is an alkylgroup of 1-10 carbon atoms, takes place according to methods known tothose skilled in the art. The 1-carboxy compounds can be reacted, forexample, by mixing a solution of the diazohydrocarbon in an inertsolvent, preferably in diethyl ether, with the 1-carboxy compound in thesame solvent or in another inert solvent, e.g., methylene chloride.After the reaction is completed (usually 1-30minutes), the solvent isremoved, and the ester is purified in the usual way. Diazoalkanes areeither known or can be prepared according to conventional methods [Org.Reactions 8:389-394 (1954)].

The ester group --OR₂ wherein R₂ is a substituted or unsubstituted arylgroup (including heterocycles) is introduced as R₁ in accordance withmethods known to persons skilled in the art. For example, the 1-carboxycompounds can be reacted with the corresponding arylhydroxy compoundswith dicyclohexylcarbodiimide in the presence of a suitable base, e.g.,pyridine or triethylamine, in an inert solvent. Solvents includemethylene chloride, ethylene chloride, chloroform, ethyl acetate,tetrahydrofuran, preferably chloroform. The reaction is conducted attemperatures of -30° to +50° C., preferably at about 10° C.

If C═C-double bonds present in the primary product are to be reduced,the hydrogenation is accomplished according to methods known per se.

The hydrogenation of the 5,6-double bond takes place conventionally atlow temperatures, preferably at about -20° C., in a hydrogen atmospherein the presence of a noble metal catalyst. A suitable catalyst is, forexample, 10% palladium on carbon.

If the 5,6- as well as the 13,14-double bonds are hydrogenated, thereaction is carried out at a higher temperature, preferably at about 20°C.

The prostaglandin derivatives of Formula I wherein R₁ is hydroxy can beconverted, using suitable amounts of the corresponding inorganic bases,into a salt, via neutralization. For example, when dissolving thecorresponding PG acids in water containing the stoichiometric quantityof the base, the solid, inorganic salt is obtained after removal of thewater by evaporation or after adding a water-miscible solvent, e.g.,alcohol or acetone.

To produce an amine salt, which is effected in the usual way, the PGacid is dissolved, for example, in a suitable solvent, e.g., ethanol,acetone, diethyl ether, acetonitrile, or benzene, and at least thestoichiometric amount of the amine is added to this solution. In thisway, the salt is ordinarily obtained in the solid phase, or it isisolated in the usual manner after evaporation of the solvent.

The amide group NHR₃ as R₁ is also introduced according to methods knownto those skilled in the art. The carboxylic acids of Formula I (R₁ =OH)are first converted into the mixed anhydride in the presence of atertiary amine, such as, for example, triethylamine, with the use of theisobutyl ester of chloroformic acid. The reaction of the mixed anhydridewith the alkali metal salt of the corresponding amide or with ammonia(R₃ =H) takes place in an inert solvent or solvent mixture, e.g.,tetrahydrofuran, dimethoxyethane, dimethylformamide,hexamethylphosphoric triamide, at temperatures of -30° to +60° C.,preferably at 0° to 30° C.

Another method for introducing the amide group NHR₃ as R₁ resides inreacting a 1-carboxylic acid of Formula I (R₁ =OH) wherein free hydroxygroups are optionally blocked intermediarily, with compounds of FormulaIV

    O═C═N--R.sub.3                                     (IV)

wherein R₃ is as defined above.

The reaction of the compound of Formula I (R₁ =OH) with an isocyanate ofFormula IV takes place optionally with the addition of a tertiary amine,e.g., triethylamine or pyridine. The reaction can be conducted without asolvent or in an inert solvent, preferably acetonitrile,tetrahydrofuran, acetone, dimethylacetamide, methylene chloride, diethylether, toluene, at temperatures of -80° to 100° C., preferably at 0° to30° C.

If the starting compound contains OH-groups in the prostane residue,then these OH-groups are also reacted. If, end products are desiredwhich contain free hydroxy groups in the prostane residue, then startingcompounds are advantageously utilized wherein these groups are blockedintermediarily by preferably readily cleavable ether or acyl residues.

All the compounds of formula II are known or are routinely preparableusing well known, fully conventional methods, e.g., as described in J.S. Binderer and R. Binderer, prostaglandin synthesis, Academic Press,New York, 1977, and in A. Mitra, The synthesis of prostaglandins,Wiley-Interscience, New York, 1977 whose disclosures are incorporated byreference herein.

As compared with PGE derivatives, the novel 9-chloroprostaglandins aredistinguished by greater stability.

The novel 9-chloroprostane derivatives of general Formula I are valuablepharmaceuticals, since they exhibit, with a similar spectrum ofactivity, a substantially improved higher specificity and, above all,substantially improved effectiveness than the corresponding naturalprostaglandins.

The novel prostaglandin analogs of this invention have a strongluteolytic effect, i.e., trigger luteolysis; moreover, significantlylower doses are required than for the corresponding naturalprostaglandins.

Also, for triggering abortions, especially upon oral administration,substantially lesser quantities of these novel prostaglandin analogs arenecessary, as compared with the natural prostaglandins.

Via conventional pharmaceutical protocols, e.g., when recording theisotonic uterus contraction in narcotized rats and on the isolated ratuterus, it can be seen that the compounds of this invention aresubstantially more active, and their activities are of longer durationthan for the natural prostaglandins.

The novel prostaglandin derivatives of this invention are also suitable,after a single enteral or parenteral administration, for inducingmenstruation or interrupting pregnancy. They are further suitable forsynchronizing the sexual cycle in female mammals, such as rabbits,cattle, horses, pigs, etc. Furthermore, the prostaglandin derivatives ofthis invention are suitable for use in preparations for diagnostic ortherapeutic interventions, e.g., cervix dilation.

The high tissue specificity of the compounds of this invention having anantifertility effect is also demonstrated by standard protocols, e.g.,studies on other smooth-muscle organs, such as, for example, on theguinea pig ileum or on the isolated rabbit trachea, where asubstantially lower stimulation is found than in case of the naturalprostaglandins. The compounds of this invention also have abronchospasmolytic effect. Additionally, they reduce the swelling of thenasal mucous membrane.

The active agents of this invention inhibit gastric acid secretion,display a cytoprotective and ulcer-healing activity, and thus counteractthe undesirable consequences of nonsteroidal antiinflammatory agents(prostaglandin synthesis inhibitors).

Several of the compounds exhibit a blood pressure lowering effect, aregulating activity in arrhythmia of the heart, and an inhibitory actionon platelet aggregation, with the conventional usage possibilitiesresulting therefrom.

For medical use, the active agents can be converted into a form suitablefor inhalation, or for oral, parenteral, or local (e.g., vaginal)administration, as is fully conventional.

Aerosol solutions can be suitably prepared for inhalation purposes.

Tablets, dragees, or capsules are suitable, for example, for oraladministration.

For parenteral administration, sterile, injectable, aqueous or oilysolutions are utilized.

For vaginal administration, suppositories are suitable and customary,for example.

Accordingly, the invention also concerns medicinal agents based on thecompounds of Formula I and the customary excipients and vehicles for usein treating mammals, including humans.

Conventional excipients are pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral, enteral or topicalapplication which do not deleteriously react with the active compounds.Suitable pharmaceutically acceptable carriers include but are notlimited to water, salt solutions, alcohols, gum arabic, vegetable oils,polyethylene glycols, gelatine, lactose, amylose, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy-methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired, mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,flavoring and/or aromatic substances and the like which do notdeleteriously react with the active compounds.

For enteral application, particularly suitable are tablets, dragees,suppositories or capsules having talc and/or carbohydrate carrier orbinder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch. A syrup, elixir or the like can be usedwherein a sweetened vehicle is employed. Sustained release compositionscan be formulated including those wherein the active compound isprotected with differentially degradable coatings, e.g., bymicroencapsulation, multiple coatings, etc.

The active agents of this invention thus can be used in conjunction withthe excipients known and conventional in galenic pharmacy, for example,for the production of preparations to trigger abortion, to control themenstrual cycle, to induce labor, or to treat hypertonia. For thesepurposes, but also for other applications mentioned above, thepreparations can contain unit doses of 0.01-50 mg of the activecompound. Daily doses are generally 0.1-50 μg/kg and administration canbe analogous to the known agents PGE₂ and 16-phenoxy-prostaglandin-E₂-methanesulfonamide, e.g., as abortive agents or agents for cervixdilatation.

Dosages for a given host can be determined, e.g., by customarycomparison of the activities of the subject compound and of a knownagent by means of an appropriate, conventional pharmacological protocol.

The novel prostaglandin analogs of this invention are substantially moreselective with regard to potency, as compared with known PG analogs incausing prostaglandin-like biological responses, and have asubstantially longer duration of biological activity. Accordingly, eachof these novel prostaglandin analogs is surprisingly and unexpectedlymore useful than one of the corresponding conventional prostaglandinsfor at least one of the pharmacological purposes indicated above becauseit has a different and narrower spectrum of biological potency than theknown prostaglandin, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than when theprostaglandin is used for the same purpose. Moreover, because of itsprolonged activity, fewer and smaller doses of the novel prostaglandinanalog are frequently effective in attaining the desired result.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingexamples, all temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

EXAMPLE 1(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy17,18,19,20-tetranor-5,13-prostadienoicAcid Methyl Ester

At 0° C., 3.8 g of p-toluenesulfonic acid chloride is added to asolution of 5.72 g of(5Z,13E)-(9S,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicacid methyl ester (prepared from the corresponding acid in methylenechloride with 0.5-molar ethereal diazomethane solution at 0° C.) in 17ml of pyridine; the mixture is agitated for 16 hours at ice bathtemperature and 48 hours at room temperature. Then the mixture iscombined with 15 ml of water, stirred for 2.5 hours at room temperature,mixed with 1 liter of ether, shaken in succession with water, 5%sulfuric acid, 5% sodium bicarbonate solution, and water, then driedover magnesium sulfate and evaporated under vacuum, thus obtaining 6.56g of the 9-tosylate as a colorless oil.

IR: 2950, 2875, 1733, 1600, 1590, 1496, 1365, 1240, 974 cm⁻¹.

A solution of 3.6 g of the 9-tosylate in 150 ml of dimethylformamide isagitated for 4 hours with 2.1 g of lithium chloride at 60° C. underargon. The mixture is subsequently poured on 10% sodium chloridesolution, extracted three times with a mixture of ether/hexane 1+1, theorganic extract is shaken three times with water, dried over magnesiumsulfate, and evaporated under vacuum.

During this step, 2.9 g of the 9β-chloro compound is obtained as acolorless oil.

IR: 2955, 1734, 1603, 1591, 978 cm⁻¹.

To split off the tetrahydropyranyl ether, 2.9 g of the above-obtainedcrude product is stirred for 16 hours at room temperature with 80 ml ofa mixture of acetic acid/water/tetrahydrofuran (65+35+10) and thenevaporated under vacuum. The residue is purified by chromatography onsilica gel. With ether as the eluent, 1.1 g of the title compound isobtained as a colorless oil.

IR: 3600, 3400 (broad), 2940, 1730, 1603, 1591, 975 cm⁻¹.

EXAMPLE 2(5z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid

450 mg of the methyl ester prepared according to Example 1 is stirredfor 5 hours with 15 ml of a solution of potassium hydroxide in ethanoland water (preparation: 2 g of potassium hydroxide is dissolved in 75 mlof ethanol and 25 ml of water). The mixture is then acidified with 10%citric acid solution to pH 4, extracted three times with methylenechloride, the organic extract is washed once with brine, dried overmagnesium sulfate, and evaporated under vacuum Chromatography of theresidue on silica gel with methylene chloride/methanol as the eluentyields 405 mg of the title compound as a colorless oil.

IR: 3600, 3400 (broad), 2930, 2855, 1710, 1600, 1590, 971 cm⁻¹

EXAMPLE 3(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Methyl Ester

At 0° C., 720 mg of p-toluenesulfonic acid chloride is added to asolution of 1.15 g of(13E)-(9S,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid methyl ester (prepared from the corresponding acid in methylenechloride with 0.5-molar ethereal diazomethane solution at 0° C.) in 3.5ml of pyridine; the mixture is stirred for 16 hours at 0° C. and for 48hours at 25° C. Subsequently, the mixture is combined with 0.3 ml ofwater, agitated for 2,5 hours at 25° C., mixed with ether, shaken insuccession with water, 5% sulfuric acid, 5% sodium bicarbonate solution,and water, and dried over magnesium sulfate, whereafter the mixture isevaporated under vacuum. Yield: 1.4 g of the 9-tosylate as a colorlessoil.

IR: 2950, 2873, 1732, 1600, 1591, 1495, 1365, 1240, 975 cm⁻¹.

A solution of 0.92 g of the 9-tosylate in 60 ml of dimethylformamide isagitated for 4 hours with 550 mg of lithium chloride at 60° C. underargon. The mixture is then poured on 10% sodium chloride solution,extracted three times with a mixture of ether/hexane 1+1, the organicextract is shaken three times with water, dried over magnesium sulfate,and evaporated under vacuum, thus obtaining 0.72 g of the 9β-chlorocompound as a colorless oil.

IR: 2955, 1733, 1602, 1590, 978 cm⁻¹.

To split off the tetrahydropyranyl ether, 0.72 g of the above-obtainedcrude product is agitated for 16 hours at 25° C. with 15 ml of a mixtureof acetic acid/water/tetrahydrofuran (65+35+10) and then evaporatedunder vacuum. The residue is purified by chromatography on silica gel.With ether as the eluent, 0.29 g of the title compound is obtained as acolorless oil.

IR: 3600, 3400 (broad), 2945, 1731, 1602, 1590, 976 cm⁻¹.

EXAMPLE 4(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid

Analogously to Example 2, 0.25 g of the methyl ester produced byfollowing Example 3 yields 0.19 g of the title compound as a colorlessoil.

IR: 3600, 3420 (broad), 2935, 2857, 1710, 1600, 1592, 972 cm⁻¹.

EXAMPLE 5(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicAcid Methyl Ester

A solution of 2.95 g of(5Z,13E)-(9S,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(m-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicacid methyl ester (prepared from the corresponding acid in methylenechloride with 0.5-molar diazomethane solution at 0° C.) in 8 ml ofpyridine is combined at 0° C. with 1.9 g of p-toluenesulfonic acidchloride; the mixture is stirred for 16 hours at ice bath temperatureand 48 hours at room temperature. Subsequently the mixture is combinedwith 5 ml of water, agitated for 2.5 hours at room temperature, mixedwith 0.4 l of ether, shaken in succession with water, 5% sulfuric acid,5% sodium bicarbonate solution, and water, dried over magnesium sulfate,and evaporated under vacuum, thus obtaining 3.4 g of the 9-tosylate as acolorless oil.

IR: 2955, 2873, 1733, 1600, 1588, 972 cm⁻¹.

A solution of 3.4 g of the 9-tosylate in 150 ml of dimethylformamide isagitated for 4 hours with 2.0 g of lithium chloride at 60° C. underargon. The mixture is then poured on 10% sodium chloride solution,extracted three times with a mixture of ether/hexane 1+1, the organicextract is shaken three times with water, dried over magnesium sulfate,and evaporated under vacuum, thus obtaining as the crude product 2.7 gof the 9β-chloro compound in the form of a colorless oil.

IR: 2955, 1733, 1600, 1587, 975 cm⁻¹.

To split off the tetrahydropyranyl ether, 2.7 g of the above-obtainedcrude product is stirred for 16 hours at room temperature with 70 ml ofa mixture of acetic acid/water/tetrahydrofuran (65+35+10) and thenevaporated under vacuum. Purification of the residue on silica gelyields, with ether as the eluent, 0.95 g of the title compound as acolorless oil.

IR: 3600, 3420 (broad), 2940, 1732, 1600, 1588, 976 cm⁻¹.

EXAMPLE 6(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicAcid

Analogously to Example 2, 510 mg of the methyl ester prepared accordingto Example 5 yields 460 mg of the title compound as a colorless oil.

IR: 3600, 3400 (broad), 2940, 2860, 1710, 1600, 1588, 973 cm⁻¹.

EXAMPLE 7(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicAcid Methyl Ester

A solution of 600 mg of(13E)-(9S,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicacid methyl ester (prepared by hydrogenating(5Z,13E)-(9S,11R,15R)-9-hydroxy-11,15-bis-(tetrahydropyran-2-yloxy)-16-(m-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicacid methyl ester in ethyl acetate at 20° C. in palladium 10% on carbonand one equivalent of hydrogen) in 2 ml of pyridine is combined at 0° C.with 390 mg of p-toluenesulfonic acid chloride, agitated for 16 hours atice bath temperature and for 48 hours at room temperature, and thencombined with 0.5 ml of water. The mixture is agitated for 3 hours atroom temperature, diluted with ether, shaken in succession with water,5% sulfuric acid, 5% sodium bicarbonate solution, and water, dried overmagnesium sulfate, and evaporated under vacuum, thus obtaining 680 mg ofthe 9-tosylate as a colorless oil.

IR: 2955, 2873, 1732, 1600, 1588, 974 cm⁻¹.

A solution of 680 mg of the 9-tosylate in 15 ml of dimethylformamide isagitated for 4 hours with 220 mg of lithium chloride at 60° C. underargon. The mixture is then poured on 10% sodium bicarbonate solution,extracted three times with a mixture of ether/hexane 1+1, the organicextract is shaken three times with water, dried over magnesium sulfate,and evaporated under vacuum, thus obtaining as the crude product 520 mgof the 9β-chloro compound in the form of an oil.

IR: 2955, 1732, 1600, 1588, 975 cm⁻¹.

To split off the tetrahydropyranyl ether, 520 mg of the above-obtainedcrude product is stirred for 16 hours at room temperature with 10 ml ofa mixture of acetic acid/water/tetrahydrofuran (65+35+10) and thenevaporated under vacuum. After purifying the residue on silica gel withether as the eluent, 225 mg of the title compound is obtained as acolorless oil.

EXAMPLE 8(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicAcid

In analogy to Example 2, 200 mg of the methyl ester prepared accordingto Example 7 yields 165 mg of the title compound as a colorless oil.

IR: 3600, 3420 (broad), 2944, 2860, 1710, 1600, 1588, 975 cm⁻¹.

EXAMPLE 9(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostadienoicAcid Methyl Ester

A solution of 1.3 g of(5Z,13E)-(9S,11R,15R)-16,16-dimethyl-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoicacid methyl ester, 800 mg of triphenylphosphine, and 370 mg of carbontetrachloride in 6 ml of acetonitrile is agitated for 2 hours at 80° C.Thereafter the mixture is diluted with 40 ml of water, extracted threetimes with a mixture of ether/hexane (1+1), the organic extract iswashed with water, dried over magnesium sulfate, and evaporated undervacuum. Chromatography of the evaporation residue on silica gel yields,with hexane/ether 4+1, 0.55 g of the 9β-chloro compound as a colorlessoil.

IR: 2960, 1733, 976 cm⁻¹.

For tetrahydropyranyl ether cleavage, 0.5 g of the above-obtained9β-chloro compound is agitated with 5 ml of a mixture of aceticacid/water/tetrahydrofuran (65+35+10) and then evaporated under vacuum.The residue is purified by chromatography on silica gel. With ether asthe eluent, 0.35 g of the title compound is obtained as a colorless oil.

IR: 3600, 3400 (broad), 2945, 1732, 976 cm⁻¹.

EXAMPLE 10(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostadienoicAcid

Analogously to Example 2, 0.3 g of the methyl ester prepared accordingto Example 9 yields 0.24 g of the title compound as a colorless oil.

IR: 3600, 3420 (broad), 2944, 1709, 975 cm⁻¹.

EXAMPLE 11(5Z,13E)-(9R,11R,16RS)-9-Chloro-11,15α-dihydroxy-16-methyl-5,13-prostadienoicAcid Methyl Ester

At 0° C., 760 mg of p-toluenesulfonic acid chloride is added to asolution of 1.1 g of(5Z,13E)-(9S,11R,16RS)-9-hydroxy-16-methyl-11,15α-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoicacid methyl ester (produced from the corresponding acid in methylenechloride with 0.5-molar diazomethane solution at 0° C.) in 3.5 ml ofpyridine; the mixture is agitated for 16 hours at 0° C. and for 48 hoursat 25° C. After the mixture has been worked up as described in Example1, 1.4 g of the 9-tosylate is obtained as a colorless oil.

IR: 2955, 2870, 1732, 975 cm⁻¹.

A solution of 1.4 g of the 9-tosylate in 60 ml of dimethylformamide isagitated for 4 hours with 840 mg of lithium chloride at 60° C. underargon. The usual working-up procedure yields 1.1 g of the 9β-chlorocompound as an oil.

IR: 2960, 1732, 975 cm⁻¹.

To split off the tetrahydropyranyl ether, 1.1 g of the above-obtainedcrude product is stirred for 16 hours at room temperature with 35 ml ofa mixture of acetic acid/water/tetrahydrofuran (65+35+10) and thenevaporated under vacuum. After chromatography of the residue on silicagel, using ether as the eluent, 0.6 g of the title compound is obtainedas an oil.

IR: 3600, 3420 (broad), 2950, 1733, 976 cm⁻¹.

EXAMPLE 12(5Z,13E)-(9R,11R,16RS)-9-Chloro-11,15α-dihydroxy-16-methyl-5,13-prostadienoicAcid

Analogously to Example 2, 0.5 g of the methyl ester produced accordingto Example 11 yields 0.39 g of the title compound as a colorless oil.

IR: 3600, 3400 (broad), 2945, 1710, 976 cm⁻¹.

EXAMPLE 13(5Z,13E)-(9R,11R,15S)-9-Chloro-11,15-dihydroxy-15-methyl-5,13-prostadienoicAcid Methyl Ester

At 0° C., 691 mg of p-toluenesulfonic acid chloride is added to asolution of 1 g of(5Z,13E)-(9S,11R,15S)-9-hydroxy-15-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoicacid methyl ester (prepared from the corresponding acid in methylenechloride with 0.5-molar diazomethane solution) in 3.5 ml of pyridine;the mixture is stirred for 16 hours at 0° C., then for 48 hours at 25°C. After the mixture has been worked up according to Example 1, 1.25 gof the 9-tosylate is obtained as a colorless oil.

IR: 2950, 2870, 1735, 1601, 1365, 1175, 978, 905 cm⁻¹.

A solution of 1.20 g of the 9-tosylate in 50 ml of dimethylformamide isagitated for 4.5 hours with 720 mg of lithium chloride at 60° C. underargon. The mixture is worked up according to Example 1, thus obtaining900 mg of the 9β-chloro compound as an oil.

IR: 2955, 2868, 1735, 978 cm⁻¹.

To split off the blocking groups, 800 mg of the thus-obtained 9β-chlorocompound is stirred with 20 ml of a mixture of aceticacid/water/tetrahydrofuran (65+35+10) for 20 hours at 25° C. Evaporationunder vacuum and chromatography of the residue on silica gel withmethylene chloride yield 400 mg of the title compound as an oil.

IR: 3600, 3420 (broad), 2955, 2870, 1735, 976 cm⁻¹.

EXAMPLE 14(5Z,13E)-(9R,11R,15S)-9-Chloro-11,15-dihydroxy-15-methyl-5,13-prostadienoicAcid

In analogy to Example 2, 300 mg of the methyl ester prepared accordingto Example 13 yields 230 mg of the title compound as an oil.

IR: 3600, 3400, 2950, 1710, 978 cm⁻¹.

EXAMPLE 15(5Z,13E)-(9R,11R,15R,16RS)-9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoicAcid Methyl Ester

A mixture of 1.2 g of(5Z,13E)-(9S,11R,15R,16RS)-9-hydroxy-16-fluoro-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoicacid methyl ester (prepared from the corresponding acid in methylenechloride with 0.5-molar diazomethane solution at 0° C.), 800 mg ofp-toluenesulfonic acid chloride, and 4 ml of pyridine is agitated for 16hours at 0° C., then for 48 hours at 25° C. The mixture is worked upaccording to Example 1. Yield: 1.45 g of the 9-tosylate as an oil.

IR: 2952, 2870, 1732, 1601, 1360, 1170, 978, 906 cm⁻¹.

1.25 g of the thus-obtained tosylate is heated with 725 mg of lithiumchloride in 50 ml of dimethylformamide under agitation for 4 hours to60° C. After the mixture has been worked up according to Example 1, 925mg of the 9β-chloro compound is obtained as an oil.

IR: 2950, 1735, 976 cm⁻¹.

To split off the blocking groups, 900 mg of the thus-produced 9β-chlorocompound is stirred with 25 ml of a mixture of glacial aceticacid/water/tetrahydrofuran (65+35+10) for 20 hours at 25° C. Evaporationunder vacuum and chromatography of the residue on silica gel withmethylene chloride yield 450 mg of the title compound as an oil.

IR: 3605, 3420, 2952, 2868, 1735, 978 cm⁻¹.

EXAMPLE 16(5Z,13E)-(9R,11R,15R,16RS)-9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoicAcid

Analogously to Example 2, 400 mg of the methyl ester produced accordingto Example 15 yields 310 mg of the title compound as an oil.

IR: 3600, 3400, 2952, 2860, 1712, 978 cm⁻¹.

EXAMPLE 17(5Z,13E)-(9S,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid Methyl Ester

A solution of 910 mg of(5Z,13E)-(9R,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprostadienoicacid methyl ester, 560 mg of triphenylphosphine, and 260 mg of carbontetrachloride in 5 ml of acetonitrile is heated for 2 hours to 80° C.For working up purposes, the mixture is diluted with 100 ml of water,extracted three times with respectively 50 ml of n-heptane, the organicextract is washed with brine, dried over magnesium sulfate, andevaporated under vacuum. The residue is chromatographed on silica gelwith hexane/ether (2+1), thus obtaining 510 mg of the 9α-chloro compoundas an oil.

IR: 2955, 2870, 1735, 1600, 1590, 1100, 980 cm⁻¹.

To split off the blocking groups, the compound is treated with theacetic acid mixture corresponding to Example 1, thus obtaining 300 mg ofthe title compound as an oil.

IR: 3600, 3400, 2950, 1735, 1601, 1590, 976 cm⁻¹.

The methyl ester of(5Z,13E)-(9R,11R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranorprostadienoicacid used as the starting material is prepared as follows:

A solution of 3 g of the 9-tosylate obtained according to Example 1 in100 ml of dimethyl sulfoxide is heated with 6 g of potassium nitrite for3 hours to 60° C. After cooling, the mixture is diluted with 800 ml ofwater, extracted three times with respectively 100 ml of hexane/ether(2+1), the combined extracts are washed twice with respectively 20 ml ofbrine, dried over magnesium sulfate, and evaporated under vacuum. Theresidue is purified on silica gel with hexane and increasing ethylacetate gradients. Yield: 1.5 g of (9R)-9β-hydroxy compound as an oil.

EXAMPLE 18(5Z,13E)-(9S,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid

Analogously to Example 2, 250 mg of the compound prepared according toExample 17 yields 190 mg of the title compound as an oil.

IR: 3600, 3410, 2960, 2870, 1710, 1600, 1588, 978 cm⁻¹.

EXAMPLE 19(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid Methylsulfonamide

A solution of 200 mg of(5Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicacid in 5 ml of dimethylformamide is combined at 0° C. with 80 mg of thebutyl ester of chloroformic acid and 60 mg of triethylamine. After 30minutes, 234 mg of the sodium salt of methylsulfonamide (prepared frommethylsulfonamide and sodium methylate) and 2 ml of hexamethylphosphorictriamide are added, and the mixture is stirred for 3 hours at 20° C.Subsequently, the reaction mixture is poured on a citrate buffer (pH 5),extracted repeatedly with ethyl acetate, the organic phase washed withbrine, dried over magnesium sulfate, and evaporated under vacuum. Afterchromatography of the residue on silica gel with methylene chloride, 80mg of the title compound is obtained as an oil.

IR: 3600, 3400, 1718, 1600, 1590, 1125, 972 cm⁻¹.

EXAMPLE 20(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Methylsulfonamide

Analogously to Example 19, the compound prepared according to Example 4yields the title compound in the form of an oil.

IR: 3605, 3410, 1720, 1600, 1588, 1125, 970 cm⁻¹.

EXAMPLE 21(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chylorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicAcid Methylsulfonamide

Analogously to Example 19, the compound produced by following Example 6yields the title compound as an oil.

IR: 3602, 3400, 1720, 1602, 1590, 1130, 970 cm⁻¹.

EXAMPLE 22(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicAcid Methylsulfonamide

In analogy to Example 19, the compound prepared according to Example 8produces the title compound in the form of an oil.

IR: 3602, 3400, 2960, 2870, 1720, 1601, 1590, 1125, 970 cm⁻¹.

EXAMPLE 23(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostadienoicAcid Methylsulfonamide

A solution of 585 mg of(5Z,13E)-(9R,11R,15R)-9-chloro-16,16-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoicacid (obtained from the methyl ester--see Example 9--by saponificationwith 1-molar sodium hydroxide solution in methanol) in 25 ml oftetrahydrofuran is combined with 0.75 mg of methanesulfonyl isocyanatein 10 ml of tetrahydrofuran and agitated for 6 hours at 20° C. Themixture is then neutralized with acetic acid, concentrated under vacuum,the residue is dissolved in 100 ml of methylene chloride, shaken withsaturated sodium bicarbonate solution and with water, dried overmagnesium sulfate, and evaporated under vacuum.

To split off the blocking groups, the residue is stirred for 4 hours at40° C. with 10 ml of a mixture of glacial aceticacid/water/tetrahydrofuran (65+35+10), evaporated under vacuum, and theresidue absorbed on 20 g of silica gel. By elution with hexane/ethylacetate (1+1), impurities are separated. With ethyl acetate, 200 mg ofthe title compound is then eluted in the form of an oil.

IR: 3600, 3420, 2955, 2868, 1718, 1120, 972 cm⁻¹.

EXAMPLE 24(5Z,13E)-(9R,11R,16RS)-9-Chloro-11,15α-dihydroxy-16-methyl-5,13-prostadienoicAcid Methylsulfonamide

Analogously to Example 19, the compound prepared according to Example 12yields the title compound as an oil.

IR: 3602, 3400, 1718, 1120, 972 cm⁻¹.

EXAMPLE 25(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid Isopropylsulfonamide

200 mg of(5Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicacid (from Example 2) is dissolved in 5 ml of dimethylformamide andcombined at 0° C. with 80 mg of the isobutyl ester of chloroformic acidand 60 mg of triethylamine. After 30 minutes, 290 mg of the sodium saltof isopropylsulfonamide (prepared from isopropylsulfonamide and sodiummethylate) and 2 ml of hexamethylphosphoric triamide are added thereto,and the mixture is stirred for 3 hours at 25° C. To work up the mixture,it is poured on 100 ml of citrate buffer (pH 5), extracted repeatedlywith ethyl acetate, the organic phase washed with brine, dried overmagnesium sulfate, and evaporated under vacuum. After chromatography ofthe residue on silica gel with methylene chloride, 91 mg of the titlecompound is obtained as an oil.

IR: 3600, 3410, 2960, 2870, 1722, 1601, 1588, 1120, 974 cm⁻¹.

EXAMPLE 26(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Isopropylsulfonamide

In analogy to Example 25, 200 mg of(13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid (preparation see Example 4) yields 85 mg of the title compound asan oil.

IR: 3605, 3410, 2955, 2865, 1722, 1600, 1588, 1125, 974 cm⁻¹.

EXAMPLE 27(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid Acetylamide

At 25° C., 150 mg of triethylamine is added to a solution of 575 mg of(5Z,13E)-(9R,11R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicacid (prepared from the corresponding methyl ester--see Example 1--bysaponification with 1-molar sodium hyroxide solution in methanol) in 15ml of acetonitrile; the mixture is cooled to 0° C., and a solution of106 mg of acetyl isocyanate in 10 ml of acetonitrile is added dropwise.Thereafter the mixture is stirred for 2 hours at 25° C., concentratedunder vacuum, diluted with 100 ml of water, adjusted to pH 5 by adding1N sulfuric acid, extracted repeatedly with ether, and the organic phasewashed with brine, dried over magnesium sulfate, and evaporated undervacuum. To split off the blocking group, the residue is stirred for 5hours at 40° C. with 15 ml of glacial acetic acid/water/tetrahydrofuran(65+35+10) and then evaporated to dryness under vacuum. The residue ischromatographed on silica gel with methylene chloride/1% isopropylalcohol, thus obtaining 220 mg of the title compound as an oil.

IR: 3600, 3400, 2945, 2862, 1708, 1600, 1588, 976 cm⁻¹.

EXAMPLE 28(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Acetylamide

Analogously to Example 27, 450 mg of(13E)-(9R,11R,15R)-9-chloro-11,15-bis(tetrahydroyran-2-yloxy)-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid (prepared from the corresponding methyl ester--see Example 3--bysaponification with 1-molar sodium hydroxide solution in methanol)yields 200 mg of the title compound as an oil.

IR: 3600, 3410, 2950, 2860, 1706, 1600, 1590, 976 cm⁻¹.

EXAMPLE 29(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicAcid Acetylamide

In analogy to Example 27, 485 mg of(13E)-(9R,11R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicacid (prepared from the corresponding methyl ester--see Example 7--bysaponification with 1-molar sodium hydroxide solution in methanol)yields 225 mg of the title compound as an oil.

IR: 3600, 3400, 2948, 2858, 1706, 1602, 1590, 976 cm⁻¹.

EXAMPLE 30(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicAcid Amide

400 mg of(5Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadienoicacid (preparation see Example 2) is dissolved in 10 ml oftetrahydrofuran and combined at 0° C. with 140 mg of triethylamine and171 mg of the isobutyl ester of chloroformic acid. After 1 hour, gaseousammonia is introduced at 0° C. for 10 minutes, and then the mixture isallowed to stand for 1 hour at 25° C. Subsequently, the mixture isdiluted with 50 ml of water, extracted three times with respectively 50ml of methylene chloride, the combined extracts are shaken once with 20ml of brine, dried over magnesium sulfate, and evaporated under vacuum.For purifying purposes, the residue is chromatographed on silica gelwith chloroform/ethyl acetate mixtures, thus obtaining 310 mg of thetitle compound as a waxy mass.

IR: 3600, 3535, 3415, 2995, 2930, 2860, 1675, 1600, 1588, 972 cm⁻¹.

EXAMPLE 31(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Amide

Analogously to Example 30, the title compound in the form of an oil isobtained from the acid prepared according to Example 4.

IR: 3600, 3535, 3410, 2996, 2930, 2860, 1670, 1601, 1588, 972 cm⁻¹.

EXAMPLE 32(5Z,13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoicAcid Amide

In analogy to Example 30, the acid prepared according to Example 6yields the title compound in the form of an oil.

IR: 3600, 3450, 2998, 2930, 2862, 1670, 1600, 1585, 974 cm⁻¹.

EXAMPLE 33(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-(m-chlorophenoxy)-17,18,19,20-tetranor-13-prostenoicAcid Amide

Analogously to Example 30, the acid produced according to Example 8yields the title compound as an oil.

IR: 3600, 3420, 2998, 2935, 2860, 1672, 1600, 1588, 972 cm⁻¹.

EXAMPLE 34(13E)-(9R,11R,15R)-9-Chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicAcid Tris(hydroxymethyl)aminomethane Salt

At 65° C., a solution of 122 mg of tris(hydroxymethyl)-aminomethane in0.4 ml of water is added to a solution of 410 mg of(13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-13-prostenoicacid (preparation see Example 4) in 70 ml of acetonitrile. The mixtureis allowed to cool down under stirring, decanted from the solvent after16 hours, and the residue dried under vacuum, thus obtaining 365 mg ofthe title compound as a white, waxy mass.

EXAMPLE 35(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-5,13,18-prostatrienoicAcid

Under argon, 915 mg of(5Z,13E)-(8R,9R,11R,12R,-15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicacid was stirred at room temperature for 17 hours with 19 ml of amixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture wasevaporated thereafter under vacuum and the residue purified by columnchromatography on silanized silica gel with ethanol/water (1:1), thusobtaining 94 mg of the title compound.

IR (Film): 3370 (broad), 1710 cm⁻¹

The starting material for the above title compound was produced asfollows:

(35a)(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicAcid Methyl Ester

A solution of 1.09 g of(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicacid methyl ester, 760 mg of triphenylphosphine, and 14.5 ml of asolution of 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48ml of acetonitrile were agitated under argon at room temperature for 69hours. The mixture was then diluted with 15 ml of ether and 30 ml ofhexane, further stirred for 10 minutes, and filtered. The residue fromthe evaporation was extracted with a mixture of 5 ml of ether and 95 mlof hexane, filtered, and evaporated to dryness under vacuum. The residuewas purified by column chromatography on silica gel with hexane/20-33%ethyl acetate as the eluent, thus isolating 1.04 g of the desiredcompound.

IR (Film): 1740, 1132, 1080, 1035, 1025, 975 cm⁻¹

(35b)(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicAcid

942 mg of the ester obtained according to the above directions wasintroduced into 16.2 ml of a solution of 3.6 g of potassium hydroxide,24 ml of water, and 120 ml of methanol, and the mixture was agitated atroom temperature for 7.5 hours. The reaction mixture was then dilutedwith water, washed with ether, and subsequently acidified at about 5° C.to pH 5 with 10% citric acid solution. The mixture was then extractedfive times with methylene chloride, the combined organic extracts werewashed with saturated sodium chloride solution, dried over magnesiumsulfate, and concentrated under vacuum. The residue from the evaporation(915 mg) could be utilized without further purification in thesubsequent reaction stage.

EXAMPLE 36(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-5,13,18-prostatrienoicAcid

A solution of 144 mg of(5Z,13E)-(8R,9S,11R,-12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicacid in 2 ml of absolute ethanol was combined with 6.4 mg of pyridinep-toluenesulfonate and agitated for 5 days at room temperature underargon. The reaction mixture was then diluted with 100 ml of methylenechloride, washed twice with saturated sodium chloride solution, driedover magnesium sulfate, and evaporated to dryness under vacuum. Theresidue was purified by column chromatography on silica gel withhexane/50-100% ethyl acetate as the eluent, thus obtaining 42.5 mg ofthe desired carboxylic acid as a highly viscous oil.

IR (Film): 3390 (broad), 1710 cm⁻¹

The starting material for the above title compound was produced asfollows:

(36a)(5Z,13E)-(8R,11R,12R,15S,16RS)-9-Oxo-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-protatrienoicAcid Methyl Ester

A solution of 1.23 g of(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicacid methyl ester in 20 ml of absolute acetone was combined at -20° C.with 1.54 ml of Jones reagent. The mixture was allowed to rest at thistemperature for 45 minutes, then combined dropwise with 2 ml ofisopropanol, stirred for 10 minutes, diluted with ether, and washedthree times with saturated sodium chloride solution. The organic phasewas dried over magnesium sulfate and concentrated to dryness undervacuum. The residue was utilized in the subsequent reaction stagewithout further purification, thus isolating 1.16 g of ketone.

(36b)(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicAcid Methyl Ester

A solution of 1.16 g of the ketone obtained in the preceding reactionstage in 25 ml of absolute methanol was combined at 0° C. with 0.5 g (13millimoles) of sodium borohydride and left for 25 minutes at thistemperature while agitating under an argon atmosphere. The solvent wasthen removed under vacuum, the residue was combined with 20 ml of waterand extracted three times with respectively 100 ml of ether. Thecombined organic phases were washed neutral with water, dried overmagnesium sulfate, and evaporated with a forced circulation evaporator.The residue was purified by column chromatography on silica gel withhexane/50-66% ethyl acetate as the eluent. Following the less polar9α-alcohol, the desired 9β-title compound was obtained (163 mg).

(36c)(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicAcid Methyl Ester

The 163 mg of 9β-alcohol obtained in the preceding reaction stage wasagitated under argon for 19 hours at room temperature together with 114mg of triphenylphosphine and 2.17 ml of a solution of 0.97 ml of carbontetrachloride, 0.79 ml of pyridine, and 48 ml of acetonitrile. Themixture was then diluted with ether/hexane, further stirred for 10minutes, and filtered. After concentration under vacuum, the residue wasextracted with a mixture of 5 ml of ether and 95 ml of hexane, filtered,and the solvent therein was removed by means of a forced circulationevaporator. The residue was purified by column chromatography on silicagel with hexane/20% ethyl acetate as the eluent, thus obtaining 159 mgof the title compound.

(36d)(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicAcid

159 mg (0.27 mmol) of the ester obtained as described above wasintroduced into 2.8 ml of a solution of 3.6 g of potassium hydroxide, 24ml of water, and 120 ml of methanol and agitated for 6 hours at roomtemperature. The reaction mixture was then diluted with water, extractedwith ether, and subsequently acidified to pH 5 with 10% citric acidsolution at 5° C. The mixture was then extracted five times withmethylene chloride, the organic extracts were washed with saturatedsodium chloride solution, dried over magnesium sulfate, and concentratedby a forced circulation evaporator. The residue was purified by columnchromatography on silica gel with hexane/ethyl acetate (1:1), thusisolating 144 mg.

EXAMPLE 37(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-13,18-prostadienoicAcid

101 mg of(13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoicacid was stirred under argon at room temperature for 25 hours with 2 mlof a mixture of acetic acid/water/tetrahydrofuran (65/35/10). Themixture was then concentrated under vacuum and the residue purified bycolumn chromatography on silica gel with hexane/0-100% ethyl acetate asthe eluent, thus producing 31 mg of the desired carboxylic acid.

IR (Film): 3380 (broad), 2730, 2660, 1710 cm⁻¹

The starting material for the above title compound was produced asfollows:

(37a)(13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-16,19-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoicAcid Methyl Ester

A solution of 1.55 g of(13E)-(8R,9S,11R,12R,-15S,16RS)-9-hydroxy-16,19-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoicacid in methylene chloride was treated with ethereal diazomethanesolution until the evolution of nitrogen ceased and the solution assumeda permanent yellow color. After removal of excess diazomethane as wellas the solvent, the residue (1.58 g) was used without furtherpurification in the subsequent reaction stage.

(37b)(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoicAcid Methyl Ester

A solution of 804 mg of the ester obtained as described above in 10.7 mlof a solution of 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine,and 48 ml of acetonitrile was stirred under argon for 73 hours at roomtemperature with 560 mg of triphenylphosphine. Thereafter the mixturewas diluted with 16 ml of ether and 32 ml of hexane, further agitatedfor 10 minutes, filtered, and concentrated by means of a forcedcirculation evaporator. The residue from the evaporation was extractedwith a mixture of 5 ml of ether and 95 ml of hexane, filtered, andconcentrated to dryness under vacuum. The residue was purified by columnchromatography on silica gel with methylene chloride/20% ethyl acetateas the eluent, thus obtaining 225.7 mg of the title compound.

(37c)(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoicAcid

The 225.7 mg of ester obtained in the preceding reaction stage wasintroduced into 3.9 ml of a solution of 3.6 g of potassium hydroxide,2.4 ml of water, and 120 ml of methanol and agitated for 6.5 hours atroom temperature. The reaction mixture was then diluted with water,extracted with ether, and then acidified to pH 5 at 50° C. with 10%citric acid solution. Thereafter the mixture was extracted five timeswith methylene chloride, the combined organic extracts were washed withsaturated sodium chloride solution, dried over magnesium sulfate, andconcentrated by a forced circulation evaporator. The residue (212.5 mg)was utilized in the subsequent stage without further purification.

EXAMPLE 38(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-13,18-prostadienoicAcid Methylsulfonylamide

103 mg of(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoicacid methylsulfonylamide was stirred for 24.5 hours under argon at roomtemperature with 1.9 ml of a mixture of aceticacid/water/tetrahydrofuran (65/35/10). Then the mixture was concentratedunder vacuum and the residue purified by column chromatography on silicagel with hexane/0-100% ethyl acetate as the eluent, thus obtaining 34.3mg of the title compound.

The starting material for the above compound was obtained as follows:

(38a)(13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoicAcid Methylsulfonylamide

111 mg of the carboxylic acid obtained according to Example (37c) wasdissolved in 2.5 ml of absolute acetonitrile and combined under argonwith 0.04 ml of triethylamine. After cooling to -5° C., the mixture wascombined dropwise with a solution of 53 mg of methanesulfonyl isocyanatein 2.5 ml of absolute acetonitrile and thereafter stirred for 2.5 hoursat this temperature. The reaction mixture was then concentrated by aforced circulation evaporator, taken up in 1.5 ml of water, acidified topH 4 with 5% sulfuric acid, and extracted three times with respectively90 ml of ether. The combined organic phases were washed neutral withsaturated sodium chloride solution, dried over magnesium sulfate, andconcentrated to dryness under vacuum. The residue was purified by columnchromatography on silica gel with hexane/0-50% ethyl acetate as theeluent, thus obtaining 103 mg of the desired compound.

EXAMPLE 39(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-5,13,18-prostatrienoicAcid Methylsulfonylamide

156 mg of(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoicacid methylsulfonylamide was stirred for 16 hours under argon at roomtemperature with 3 ml of a mixture of acetic acid/water/tetrahydrofuran(65/35/10). The mixture was then evaporated under vacuum and the residuepurified by column chromatography on silica gel with methylenechloride/5-30% isopropanol as the eluent, thus obtaining 62 mg of thedesired compound.

IR (Film): 3480, 3360, 3260, 1710, 1340, 1150 cm⁻¹

The starting material for the title compound was produced as follows:

(39a)(5Z,13E)-(8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic Acid Methylsulfonylamide

198 mg of the carboxylic acid produced according to Example (35b) wasdissolved in 4.3 ml of absolute acetonitrile and combined under argonwith 0.066 ml of triethylamine. After cooling to -5° C., the mixture wascombined dropwise with a solution of 95 mg of methanesulfonyl isocyanatein 4.3 ml of absolute acetonitrile and thereafter stirred at thistemperature for 2.25 hours. The reaction mixture was then taken up in2.8 ml of water, acidified to pH 4 with 5% sulfuric acid, and extractedthree times with respectively 90 ml of ether. The combined organicphases were washed neutral with saturated sodium chloride solution,dried over magnesium sulfate, and evaporated to dryness under vacuum.The residue was purified by column chromatography on silica gel withmethylene chloride/5% isopropanol as the eluent, thus obtaining 156 mgof the title compound.

EXAMPLE 40(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-dihydroxy-16,16,19-trimethyl-5,13,18-prostatrienoicAcid

1.04 g of(5Z,13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoicacid was stirred under argon at room temperature for 19 hours with 21 mlof a mixture of acetic acid/water/tetrahydrofuran (65/35/10). Themixture was then evaporated under vacuum and the residue purified bycolumn chromatography on silica gel with hexane/0-100% ethyl acetate asthe eluent, thus obtaining 380 mg of the title compound.

IR (Film): 3360 (broad), 1710 cm⁻¹

The starting material for the above compound was produced as follows:

(40a)(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoicAcid Methyl Ester

A solution of 1.15 g of(5Z,13E)-(8R,9S,11R,12R,15R)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoicacid methyl ester, 780 mg of triphenylphosphine, and 15 ml of a solutionof 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48 ml ofacetonitrile was stirred for 55 hours under argon at room temperature.The mixture was then diluted with 15 ml of ether and 30 ml of hexane,further stirred for 10 minutes, and filtered. The residue from theevaporation was extracted with a mixture of 5 ml of ether and 95 ml ofhexane, filtered, and concentrated to dryness under vacuum. The residuewas purified by column chromatography on silica gel with hexane/20-50%ethyl acetate as the eluent, thus obtaining 1.07 g of the desiredcompound.

IR (Film): 1740, 1130, 1075, 1035, 1025, 970 cm⁻¹

(40b)(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,16,19-trimethyl-5,13,18-prostatrienoicAcid

1.07 g of the ester obtained according to the above description wasintroduced into 18 ml of a solution of 3.6 g of potassium hydroxide, 24ml of water, and 120 ml of methanol and stirred at room temperature for8 hours. The reaction mixture was then diluted with water, washed withether, and subsequently acidified to pH 5 at about 5° C. with 10% citricacid solution. The mixture is thereafter extracted five times withmethylene chloride, the combined organic extracts were washed withsaturated sodium chloride solution, dried over magnesium sulfate, andconcentrated under vacuum. The residue from the evaporation (1.04 g)could be utilized without further purification in the subsequentreaction stage.

EXAMPLE 41(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-dihydroxy-16,16,19-trimethyl-5,13,18-prostatrienoicAcid Methyl Ester

100 mg of the carboxylic acid obtained according to Example 40 wasdissolved in methylene chloride and combined with such a quantity ofethereal diazomethane solution that the nitrogen evolution ceased andthe yellow color of the solution became permanent. After evaporation ofthe excess diazomethane and of the solvent under vacuum at roomtemperature, 101 mg of the desired ester was obtained.

IR (Film): 3400 (broad), 1735 cm⁻¹

EXAMPLE 42(13E)-(8R,9R,11R,12R,15S)-9-Chloro-11,15-dihydroxy-19-methyl-13,18-prostadienoicAcid Acetylamide

460 mg of(13E)-(8R,9R,11R,12R,15R)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-19-methyl-13,18-prostadienoicacid acetylamide was stirred under argon at room temperature for 17hours with 10 ml of a mixture of acetic acid/water/tetrahydrofuran(65/35/10). The mixture was then concentrated under vacuum, and theresidue was purified by column chromatography on silica gel withhexane/0-100% ethyl acetate as the eluent, thus obtaining 197 mg of thetitle compound.

IR (Film): 3400, 1703 cm⁻¹

The starting material for the above compound was prepared as follows:

(42a)(13E)-(8R,9R,11R,12R,15S)-9-Chloro-19-methyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoicAcid Methyl Ester

A solution of 1.0 g of(13E)-(8R,9S,11R,12R,15S)-9-hydroxy-19-methyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoicacid methyl ester in 14 ml of a solution of 0.97 ml of carbontetrachloride, 0.79 ml of pyridine, and 48 ml of acetonitrile wasstirred together with 730 mg of triphenylphosphine for 70 hours at roomtemperature under argon. Thereafter the mixture was diluted with 16 mlof ether and 32 ml of hexane, further agitated for 10 minutes, filtered,and concentrated by means of a forced circulation evaporator. Theevaporation residue was extracted with a mixture of 5 ml of ether and 95ml of hexane, filtered, and concentrated to dryness under vacuum. Theresidue was purified by column chromatography on silica gel withhexane/20% ethyl acetate as the eluent, thus obtaining 720 mg of thetitle compound.

(42b)(13E)-(8R,9R,11R,12R,15S)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-19-methyl-13,18-prostadienoicAcid

The 720 mg of ester produced in the preceding reaction stage wasintroduced into 13 ml of a solution of 3.6 mg of potassium hydroxide,2.4 ml of water, and 120 ml of methanol, and agitated for 7 hours atroom temperature. The reaction mixture was then diluted with water,extracted with ether, and thereupon acidified to pH 5 at 5° C. with 10%citric acid solution. Then the mixture was extracted five times withmethylene chloride, the combined organic extracts were mixed withsaturated sodium chloride solution, dried over magnesium sulfate, andconcentrated by means of a forced circulation evaporator. The residue(630 mg) was utilized in the subsequent stage without furtherpurification.

(42c)(13E)-(8R,9R,11R,12R,15S)-9-Chloro-11,15-bis(tetrahydropyran-2-yloxy)-19-methyl-13,18-prostadienoicAcid Acetylamide

At 25° C., 170 mg of triethylamine was added to a solution of 630 mg ofthe acid obtained as described above in 17 ml of acetonitrile; themixture was cooled to 0° C. and a solution of 120 mg of acetylisocyanate in 10 ml of acetonitrile was added dropwise thereto.Subsequently the mixture was stirred for 2 hours at 25° C., concentratedunder vacuum, diluted with 100 ml of water, adjusted to pH 5 by theaddition of N sulfuric acid, and extracted several times with ether. Thecombined organic phases were washed with saturated sodium chloridesolution, dried over magnesium sulfate, and concentrated to drynessunder vacuum. The residue (460 mg) was used without further purificationin the THP ether splitting step.

EXAMPLE 43(5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-Dichloro-11,15-dihydroxy-16-methyl-5,13,18-prostatrienoicAcid

Under argon, 427 mg of(5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoicacid was stirred at room temperature for 16 hours with 9 ml of a mixtureof acetic acid/water/tetrahydrofuran (65/35/10). The mixture was thenevaporated under vacuum and the residue purified by columnchromatography on silica gel with hexane/20-80% ethyl acetate, thusproducing 180 mg of the title compound.

IR (Film): 3360 (broad), 1710 cm⁻¹

The starting material for the above title compound was prepared asfollows:

(43a)(5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-Dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoicAcid Methyl Ester

A solution of 1.16 g of(5Z,13E,18Z)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-19-chloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoicacid methyl ester, 785 mg of triphenylphosphine, and 15 ml of a solutionof 0.97 ml of carbon tetrachloride, 0.79 ml of pyridine, and 48 ml ofacetonitrile was stirred under argon at room temperature for 65 hours.The mixture was then diluted with 15 ml of ether and 30 ml of hexane,further stirred for 10 minutes, and filtered. The evaporation residuewas extracted with a mixture of 5 ml of ether and 95 ml of hexane,filtered, and concentrated to dryness under vacuum. The residue waspurified by column chromatography on silica gel with hexane/10-50% ethylacetate as the eluent. In this way, 457 mg of the desired compound wasisolated.

(43b)(5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-Dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoicAcid

457 mg of the ester obtained as described above was introduced into 7.6ml of a solution of 3.6 g of potassium hydroxide, 24 ml of water, and120 ml of methanol, and stirred for 6 hours at room temperature. Thereaction mixture was then diluted with water, washed with ether, andthereafter acidified to pH 5 at about 5° C. with 10% citric acidsolution. Then the mixture was extracted five times with methylenechloride, the combined organic extracts were washed with saturatedsodium chloride solution, dried over magnesium sulfate, and concentratedunder vacuum. The residue from the evaporation could be utilized in thesubsequent reaction stage without further purification. Yield: 427 mg ofthe title compound.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A 9-chloroprostane of the formula ##STR5##wherein the 9-chlorine atom can be in the α- or β-position,R₁ is OR₂wherein,R₂ is H; C₁₋₁₀ -alkyl; C₁₋₁₀ -alkyl substituted by halogen, C₁₋₄-alkoxy, C₆₋₁₀ -aryl or -aroyl, C₆₋₁₀ -aryl or -aroyl substituted by thesubstituents defined below for the R₂ aryl groups, di-C₁₋₄ -alkylamino,or tri-C₁₋₄ -alkylammonium; C₄₋₁₀ -cycloalkyl; C₄₋₁₀-cycloalkyl-substituted by C₁₋₄ -alkyl; C₆₋₁₀ -aryl; C₆₋₁₀ -arylsubstituted by 1-3 halogen atoms, phenyl, 1-3 C₁₋₄ -alkyl groups, or achloromethyl, fluoromethyl, trifluoromethyl, carboxy, hydroxy or C₁₋₄-alkoxy group; or an aromatic heterocycle of 5- or 6-total ring atomsand 1-2 hetero N, O or S atoms, the remainder being carbon atoms; A iscis--CH═CH--, B is --CH₂ --CH₂ --, trans--CH═CH-- or --C═C--, W ishydroxymethylene or ##STR6## wherein the OH-group in each case can be inthe α- or β-position, and can be etherified or esterified bytetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl, trimethylsilyl,dimethyl-tert-butylsilyl, tribenzylsilyl, acetyl, propionyl, butyryl orbenzoyl; D and E together represent a direct bond or D is astraight-chain or branched alkylene group of 1-10 carbon atoms,optionally substituted by fluorine, and E is a direct bond, and R₄ ishydroxy or hydroxy etherified or esterified as defined for W above; R₅is a C₁₋₁₀ -hydrocarbon aliphatic group substituted by halogen; or aphysiologically acceptable salt thereof with a base when R₁ is OH.
 2. A9-chloroprostane of the formula ##STR7## wherein the 9-chlorine atom canbe in the α- or β-positionR₁ is OR₂ wherein,R₂ is H; C₁₋₁₀ -alkyl; C₁₋₁₀-alkyl substituted by halogen, C₁₋₄ -alkoxy, C₆₋₁₀ -aryl or -aroyl,C₆₋₁₀ -aryl or -aroyl substituted by the substituents defined below forthe R₂ aryl groups, di-C₁₋₄ -alkylamino, or tri-C₁₋₄ -alkylammonium;C₄₋₁₀ -cycloalkyl; C₄₋₁₀ -cycloalkyl-substituted by C₁₋₄ -alkyl; C₆₋₁₀-aryl; C₆₋₁₀ -aryl substituted by 1-3 halogen atoms, phenyl, 1-3 C₁₋₄-alkyl groups, or a chloromethyl, fluoromethyl, trifluoromethyl,carboxy, hydroxy or C₁₋₄ -alkoxy group; or an aromatic heterocycle of 5-or 6-total ring atoms and 1-2 hetero N, O or S atoms, the remainderbeing carbon atoms; A is cis--CH═CH--, B is --CH₂ --CH₂ --,trans--CH═CH-- or --C.tbd.C--, W is hydroxymethylene or ##STR8## whereinthe OH-group in each case can be in the α- or β-position, and can beetherified or esterified by tetrahydropyranyl, tetrahydrofuranyl,α-ethoxyethyl, trimethylsilyl, dimethyl-tert-butylsilyl, tribenzylsilyl,acetyl, propionyl, butyryl or benzoyl; D and E together represent adirect bond or D is a straight-chain or branched alkylene group of 1-10carbon atoms, optionally substituted by fluorine, and E is a directbond, and R₄ is hydroxy or hydroxy etherified or esterified as definedfor W above; R₅ is unsaturated and is a C₁₋₁₀ hydrocarbon aliphaticgroup; or a C₁₋₁₀ -hydrocarbon aliphatic group substituted by halogen;or a physiologically acceptable salt thereof with a base when R₁ is OH.3. A 9-chloroprostane of the formula ##STR9## wherein the 9-chlorineatom can be in the α- or β-positionR₁ is OR₂ wherein,R₂ is H; C₁₋₁₀-alkyl; C₁₋₁₀ -alkyl substituted by halogen, C₁₋₄ -alkoxy, C₆₋₁₀ -arylor -aroyl, C₆₋₁₀ -aryl or -aroyl substituted by the substituents definedbelow for the R₂ aryl groups, di-C₁₋₄ -alkylamino, or tri-C₁₋₄-alkylammonium; C₄₋₁₀ -cycloalkyl; C₄₋₁₀ -cycloalkyl substituted by C₁₋₄-alkyl; C₆₋₁₀ -aryl; C₆₋₁₀ -aryl substituted by 1-3 halogen atoms,phenyl, 1-3 C₁₋₄ -alkyl groups, or a chloromethyl, fluoromethyl,trifluoromethyl, carboxy, hydroxy or C₁₋₄ -alkoxy group; or an aromaticheterocycle of 5- or 6-total ring atoms and 1-2 hetero N, O or S atoms,the remainder being carbon atoms; A is cis--CH═CH--, B is --CH₂ --CH₂ --or --C.tbd.C--, W is hydroxymethylene or ##STR10## wherein the OH-groupin each case can be in the α-or β-position, and can be etherified oresterified by tetrahydropyranyl, tetrahydrofuranyl, α-ethoxyethyl,trimethylsilyl, dimethyl-tert-butylsilyl, tribenzylsilyl, acetyl,propionyl, butyryl or benzoyl; D and E together represent a direct bondor D is a straight-chain or branched alkylene group of 1-10 carbonatoms, optionally substituted by fluorine, and E is a direct bond, andR₄ is hydroxy or hydroxy etherified or esterified as defined for Wabove; R₅ is a C₁₋₁₀ hydrocarbon aliphatic group; or a C₁₋₁₀-hydrocarbon aliphatic group substituted by halogen; or aphysiologically acceptable salt thereof with a base when R₁ is OH. 4.(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-dihydroxy-16,16,19-trimethyl-5,13,18-prostatrienoicacid, a compound of claim
 2. 5.(5Z,13E)-(8R,9R,11R,12R,15R)-9-Chloro-11,15-dihydroxy-16,16,19-trimethyl-5,13,18-prostatrienoicacid methyl ester, a compound of claim
 2. 6.(5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-Dichloro-11,15-dihydroxy-16-methyl-5,13,18-prostatrienoicacid, a compound of claim
 2. 7. A compound of claim 2, wherein R₅ isselected such that the 18-position of the resultant compound contains adouble bond.
 8. A method of achieving a cytoprotective effect in apatient comprising administering a cytoprotectively effective amount ofa compound of claim
 4. 9. A method of achieving a cytoprotective effectin a patient comprising administering a cytoprotectively effectiveamount of a compound of claim
 3. 10. A method of achieving acytoprotective effect in a patient comprising administering acytoprotectively effective amount of a compound of claim
 2. 11. A methodof achieving a cytoprotective effect in a patient comprisingadministering a cytoprotectively effective amount of a compound ofclaim
 1. 12. A pharmaceutical composition comprising a cytoprotectiveamount of a compound of claim 3 and a pharmaceutically acceptablecarrier.
 13. A pharmaceutical composition comprising a cytoprotectiveamount of a compound of claim 2 and a pharmaceutically acceptablecarrier.
 14. A pharmaceutical composition comprising a cytoprotectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier. 15.(5Z,13E)-(9R,11R,15R,16RS)-9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoicacid methyl ester, a compound of claim
 1. 16.(5Z,13E)-(9R,11R,15R,16RS)-9-Chloro-11,15-dihydroxy-16-fluoro-5,13-prostadienoicacid, a compound of claim
 1. 17.(5Z,13E)-8R,9R,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-5,13,18-prostatrienoicacid, a compound of claim
 2. 18.(5Z,13E)-(8R,9S,11R,12R,15S,16RS)-9-Chloro-11,15-dihydroxy-16,19-dimethyl-5,13,18-prostatrienoicacid, a compound of claim 2.